---

Wisconsin Viral Research Group, Ltd.

Physician's Corner: HHV-6

http://www.hhv6.com/

Fundamentals of HHV-6

Basic Science

 

Human herpesvirus 6 (HHV-6) is a beta-herpesvirus, first isolated from the peripheral blood of
six patients with lymphoproliferative disorders in 1986. The sixth member of the herpes family
of viruses discovered, this virus is a double-stranded DNA virus, which is most closely related
to cytomegalovirus (CMV) in terms of DNA homology. Two variants or subtypes of HHV-6 are
recognized based on DNA sequencing, cell tropism, and pathogenicity. These are designated
HHV-6A and HHV-6B. Although these variants are closely related (>90% DNA homology), there
are differences in epidemiology and pathogenicity. HHV-6 can infect and is cytolytic for
several cell types including CD4 lymphocytes (probably a primary target), CD8 cells, NK cells,
oligodendrocytes, and microglial cells. The pathogenicity of HHV-6 probably relates to several
mechanisms: cytopathic effect for the cells it infects, induction of cytokines, effects on
immune function (immune suppressive), and effects on other viruses (e.g. transactivation). As
with all herpesviruses, after primary infection, the virus becomes latent in various cells
(salivary epithelial cells, CD4 lymphocytes, monocytes, and neural cells). Subsequent infections
are a result of reactivation. Reactivation clearly occurs in the immunocompromised host.
Reactivation may also occur in normal individuals. The factors that may lead to reactivation in
the normal host are unclear (genetic, environmental, etc.).

 

The epidemiology of HHV-6 infection differs with the variant. HHV-6B is endemic and is
acquired early in childhood with rapid seroconversion after 6 months of age. Most children
seroconvert by age 2. The virus is readily found in saliva and is presumably acquired through
exposure to secretions or droplets. HHV-6A is not seen to any significant degree until
adulthood, in which an unknown but probably small percentage of adults are seropositive for this
variant. Whether past infection with HHV-6B in childhood provides protection against HHV-6A
later in life is unclear. However, there may be individuals in which cross-protection does not
occur.

Clinical

Primary infection with HHV-6B may be asymptomatic. Symptomatic HHV-6 infection in children
is the cause of roseola (exathem subitum). This is a febrile illness of early childhood that
usually lasts 3-5 days; characterized by fever, maculopapular rash, respiratory symptoms and
less commonly neurologic symptoms. Neurologic entities seen with primary HHV-6 infection
include encephalitis, meningitis, and febrile seizures. HHV-6 infection accounts for 10% of all
clinic visits in the first three years of life. Primary infection with HHV-6A is less well
understood, but can likely be asymptomatic as well as cause a viral syndrome. Reactivation of
HHV-6 infection (active/productive infection) has been associated with several syndromes in
both immunocompetent and immunocompromised hosts. In "normal" patients it has been
associated with a mononucleosis syndrome, autoimmune disorders (e.g. Sjorgren's syndrome),
focal encephalitis, demyelinating encephalitis, demyelinating myelitis, among others. In
immunocompromised patients, in particular transplant patients, these viruses can cause
encephalitis, pneumonitis, hepatitis, and bone marrow suppression. Fatal encephalitis has also
been demonstrated in HIV/AIDS cases.

 

The association with HHV-6 and multiple sclerosis is intriguing. HHV-6 has clearly been shown
to be neuroinvasive. Oligodendrocytes are a target for lytic HHV-6 infection in the CNS
tissues of patients with HHV-6 encephalitis. The histopathologic findings in AIDS patients,
transplant patients, and normal patients with HHV-6 encephalitis have shown either focal or
diffuse demyelination (ref. 9, 11, 17). The autopsy study by Challoner detected high levels of
HHV-6 DNA and viral antigens in the CNS tissues of MS patients (ref 12). Autopsy studies by
our group in MS cases demonstrated cells actively infected with HHV-6 in the
inflammatory/demyelinated lesions of the CNS tissues. In control cases (normal brains and
non-MS inflammatory CNS diseases) no active HHV-6 was found. Autopsy studies have detected
both the A and B variant in CNS tissues, however, whether one predominates (e.g. A variant) is
unresolved. A case of acute MS has been reported, which showed a demyelinating
leukoencephalitis at autopsy secondary to HHV-6 (ref. 10).

 

Soldan and associates detected HHV-6 specific IgM antibodies and HHV-6 DNA with a higher
frequency in the serum of MS patients than controls. We have found active HHV-6 infection of
the bloodstream in MS patients by rapid shell vial culture. Active HHV-6 in the bloodstream
was demonstrated in over 50% of MS cases at random screening. No positive cultures were
found in healthy controls (healthy blood donors randomly screened). Active HHV-6 infection has
been found in both autopsy cases and the bloodstream of relapsing/remitting secondary
progressive, and chronic progressive MS

 

Active HHV-6 infection has also been implicated in chronic fatigue syndrome. Several studies
have demonstrated evidence of HHV-6 in CFS patients. CFS patients have been reported with
immunologic abnormalities, neurologic features, and evidence of viral activation. HHV-6
detected by the rapid shell vial assay was positive for active infection in over 30% of CFS
patients on initial screening. Follow-up cultures in patients who initially tested negative were
subsequently positive in an additional 20% - 40% of cases. Positive cultures, as noted above,
are not seen in healthy control patients using this method.

 

Diagnosis

Serologic assays can be used to establish evidence of latent infection (i.e. past exposure). IgM
antibodies may be helpful in the diagnosis of primary infection, but are unreliable to detect
reactivation of HHV-6.

 

The detection of active HHV-6 infection is more difficult. Traditional viral cultures to assess
for cytopathic effect are cumbersome and basically a research tool. DNA detection by PCR
methodology on cellular specimens (PBMC), cannot reliably differentiate between latent and
active infection. DNA detection on acellular specimens (serum, plasma, CSF), is probably more
reliable for active infection however, the presence of "inhibitors" create significant problems
with false negative test results. Culturing for active HHV-6 using a more rapid technique by
the shell vial assay is probably the best current method for diagnosis of active infection. The
particulars of this methodology is described in the lab section of this web site. The rapid shell
vial assay has a sensitivity in the 86% range, with a specificity of nearly 100%.

 

Treatment

In vitro studies with HHV-6 have been done by several investigators. This virus is generally
considered to be resistant to acyclovir (Zovirax) with IC 50 levels unattainable using
conventional dosing regimens. The same likely applies to valacyclovir (Valtrex). Both ganciclovir
(Cytovene) and foscarnet (Foscavir) have shown in vitro activity for HHV-6 that would be
achievable with established current dosing recommendations. This would be consistent with the
large amount of data that has been collected with these drugs in the treatment of CMV
infections. Both drugs have been used successfully in the treatment of life-threatening HHV-6
infections in transplant patients. The most common adverse effect of ganciclovir is reversible
cytopenias, especially the WBC count. Foscarnet has numerous adverse effects including
nephrotoxicity, electrolyte disturbances, anemia, etc. Based on the adverse effect profile of
these drugs, ganciclovir may be a better choice between these two drugs, unless cytopenias are
a major concern. The current ganciclovir dosing regimen for CMV infections which can probably
be extrapolated to HHV-6, is 5mg/kg IV every 12 hours. Whether the dosing can be reduced to
once daily (as with CMV infections) and the duration of therapy (i.e. ongoing therapy) is unknown
and will require further study. Evidence in one MS patient that we have treated, suggests
relapse of active viremia after therapy is discontinued.

Other antiviral agents may be candidates for further study as well. The fact that interferon
(currently beta interferon) has been shown to be effective in MS in reducing relapses and
slowing progression raises questions about the specific mechanisms involved. Since interferons
have very potent antiviral activity, and are immune enhancers (T lymphocytes, NK cells), this
may explain their activity in the activated HHV-6 infection with MS cases. In assuming
activated HHV-6 infection in patients with MS, the goal of any therapy to control viral
reactivations would be the abatement of MS relapses and cessation of progression. Control of
viral reactivations would seem unlikely to reverse existing areas of neurologic damage. Clinical
trials will be important to further evaluate antiviral agents in MS and other HHV-6 related
diseases.